It has been proposed that human cancers contain cancer stem cells (CSC) that are responsible for initiating and maintaining tumor growth and also, these are resistant to therapy. However, the concept of CSC has been under siege recently. Some have argued that the concept is an artifact of using xenogeneic models, as the frequency of cancer-initiating cells appears to increase dramatically with the use of increasingly immune-deficient hosts. Perhaps a more fundamental challenge of the CSC concept is that the molecular program of CSC is not necessarily distinct from the bulk of cancer cells. For instance Wnt, Hedgehog and Bmi- 1, which are known regulators for self-renewal of CSC, are also involved in regulation of cell proliferation in general. To overcome these caveats, we have been using a spontaneous mouse lymphoma model to determine the molecular program underlying CSC functions. Of the two seminal functions of CSC, namely, self-renewal and maintenance of CSC, our recent study, which was accepted for publication in Cell Stem Cell, has established the molecular programming underlying CSC maintenance. Building on these advances, we propose to identify the programming driving CSC self-renewal and further, determine if we can use these self- renewal and maintenance programs to reprogram cancer cells back into CSC. PUBLIC HEALTH RELEVANCE: It has been proposed that human cancers contain cancer stem cells (CSC) that are responsible for initiating and maintaining tumor growth and also, these are resistant to therapy. A more fundamental challenge of the CSC concept is that the molecular program of CSC is not necessarily distinct from the bulk of cancer cells. To overcome these caveats, we have been using a spontaneous mouse lymphoma model to determine the molecular program underlying CSC functions. Of the two seminal functions of CSC, namely, self-renewal and maintenance of CSC, our recent study, which was accepted for publication in Cell Stem Cell, has established the molecular programming underlying CSC maintenance. Building on these advances, we propose to identify the programming driving CSC self-renewal and further, determine if we can use these self- renewal and maintenance programs to reprogram cancer cells back into CSC.